Current Topics in Microbiology 113 and Immunology Editors M. Cooper, Birmingham/Alabama· W. Goebel, Wiirzburg P.H. Hofschneider, Martinsried . H. Koprowski, Philadelphia F. Melchers, Basel· M. Oldstone, La JollalCalifornia RRott, GieBen . H.G.Schweiger, Ladenburg/Heidelberg P.K. Vogt, Los Angeles· RZinkernagel, ZUrich Oncogenes in B-Cell Neoplasia Workshop at the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, March 5.c... 7, 1984 Organized and Edited by M. Potter, F. Melchers, and M. Weigert With 65 Figures Springer-Verlag Berlin Heidelberg New York Tokyo 1984 Dr. MICHAEL POTTER Laboratory of Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, USA Professor Dr. FRITZ MELCHERS Basel Institute for Immunology, CH-4005 Basel, Switzerland Dr. MARTIN WEIGERT Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA ISBN -13: 978-3-642-69862-0 e-ISBN -13: 978-3-642-69860-6 DOl: 10.1007/978-3-642-69860-6 This work is subject to copyright. All rights are reserved, whether the whole or pact of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © by Springer-Verlag, Berlin Heidelberg 1984 Softcover reprint of the hardcover 1st edition 1984 Library of Congress Catalog Card Number 15-12910 The use of registered names, trademarks, etc. in this pUblication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this bo9k. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2123/3130-543210 In Memoriam Henry G. Kunkel (1916-1983) rlenry Kunkel planned to participate in this workshop. Much of his ex perimental work concerned B-cell neoplasm of man. In 1951 he, along with R.J. Slater and R.A. Good demonstrated the antigenic similarities of myeloma proteins and y-globulins (immunoglobulins), and began using tumors of B-lymphocytes as a means for understanding the normal counterparts. The antigenic relationship between myeloma and normal immunoglobulin was the foundation for the subsequent elucidation of the heavy chain classes of immunoglobulins. The individual antigenic specificities of homogeneous myeloma proteins were the next important milestone (Slater et al., 1955), and the interpretation of these specificities at flrsr-presented a perplexing problem, but ultimately provided a direct conceptual pathway to the study of antibody diversity A very logical extension of Henry Kunkel's concept of homogeneous immunoglobulins produced by clones of B-cells, was that homogeneous VI immunoglobulins could also possess functional (biological) activities, and he was among the first to find examples (Kritzman et al., 1961). The cross-specificities (shared idiotypic determinantsr-on-groups of homogeneous immunoglobulins with similar functional properties had a great influence on subsequent structural studies of v-region genes and their corresponding structures (Kunkel, 1970). Henry Kunkel inspired and trained a great number of today's most pro ductive immunologists. A measure of his influence is illustrated by the dedication of an entire issue of the Scandinavian Journal of Immu nology in September, 1976 to papers written by his students. This meeting surely owes many of its origins to the ideas of Henry Kunkel who facilitated the use of lymphoid tumors to examine normal processes by showing that many of the products of tumors were indeed similar to those made by normal counterparts. It is this familiarity that has provided a perspective for immunologists to question now, the origin of neoplastic change. Kunkel HG, Slater RJ and Good RA (1951) Relation between certain mye loma proteins and normal gammaglobulin. Proc Soc Exp 8iol Med 76: 190-193 Slater RJ, Ward SM and Kunkel HG (1955) Immunological relationships among the myeloma proteins. J Exp Med 101 :85-108 Kritzman J, Kunkel HG, McCarthy J and Mellors RC (1961) Studies of a Waldenstrom-type with rheumatoid factor properties. macroglobul~n J Lab Clin Med 57:905-917 Kunkel HG (1970) Individual antigenic specificity; cross-specificity and diversity of human antibodies. Fed Proc 29:55-58 Scandinavian Journal of Immunology (Sept 1976) 5:599-873 Preface Michael Potter, Fritz Melchers, Martin Weigert The second workshop on Mechanisms of B Cell Neoplasia was held in Bethesda, Maryland in Wilson Hall at the National Institutes of Health on March 5, 6, and 7, 1984. It followed a workshop on the same topic that was held at the Basel Institute for Immunology, March 15-17, 1983. That first meeting attempted to bring together cell biologists, experimental pathologists and molecular geneti cists interested in B cells, to discuss pathogenetic processes in the development and maintenance of the neoplastic state. The impetus for this discussion emanated from two important developments: first, the discovery of the viral promoter insertion mechanism for acti vating the myc oncogene in bursal lymphomatosis by Hayward, Neil, and Astrin;-second, the findings that the non-random chromosomal trans locations involving the immunoglobulin gene chromosomes occur red in very high frequencies in murine plasmacytomas and human Burkitt's lymphomas. During the planning stages of that meeting Shen-Ong et al. discovered that non-random translocations activated the myc oncogene. Promoter insertions and non-random trans locations were-rwo mechanisms that caused transcription of the myc oncogene messages in three different kinds of well defined experimental and clinical B cell tumors. Unregulated myc gene transcription provided the first evidence of a specific bioChemical lesion in B cell neo plasia. Immunologists have studied tumors of the B cell lineage for cellular and molecular aspects of normal B cell development, since they appear to be frozen states of various stages of this cellular development. From the comparison of normal and neoplastic B cells a wealth of data is available that provides a working basis for ex amining in detail the process of neoplastic transformation in B lymphocytes. In the intervening year between the workshops, rapid progress has been made in the elucidation of structures of oncogenes Different kinds of mutant c-oncogenes were discovered: 1) point mu tations in coding sequences, e.g., the base substituted ras genes; 2) deletion mutants, e.g., the truncated oncogenes in transforming viruses, e.g., v-abl, erbB, etc.; 3) regulatory mutants of c-myc and 4) amplified c-oncogenes. Important insights were also gaIned in the understanding of the function of these oncogenes. In partic ular the normal counterparts of some oncogenes have been identified, e.g., the v-sis homology with platelet derived growth factor, the erbB homologY-With epidermal growth factor receptor, the Tlym-I homology with HMC class I genes, the B-Iym homology with transferrin and the ras homology with the p21 sub~of the transferrin re ceptor. --- The second workshop was as exciting as the first one. We thank the participants of the meeting for promptly submitting their manu scripts. This reflects, we think, the enthusiasm that pervaded this meeting and we are grateful that the proceedings can be published in such a short time. Rapid publication requires an efficient pub lisher. We therefore are indebted to Springer Verlag and their re presentative, Mr John Morgan, New York, for their interest, care and speed in editing and publishing these proceedings. We are grateful to Ms Marion Millhouse of CSR, Inc., and Ms Victoria Rogers, manager of the Laboratory of Genetics, for organizing the meeting, making the local arrangements, assembling the manuscripts VIII and for working out all the demanding details of th& meeting in a seemingly effortless way. Last, not least, the organizers of the meeting thank the National Cancer Institute for sponsoring the meet ing, and Dr Alan S. Rabson, Director, Division of Cancer Biology and Diagnosis, for his enthusiastic support. It is anticipated that the future will bring an even better under standing of the role of oncogenes in the process of B cell neoplasia This, in turn, should advance our understanding of the physiology and biochemistry of growth regulation of normal B lymphocytes. We are looking forward to the third workshop of this series in 1985, hoping that it will then still be possible to convene a represent ative selection of the major groups working in this fast moving field of biology and medicine as, we hope, we have done in 1984. Table of Contents Cooperation of Oncogenes in B-Cell Neoplasia G. Klein: Introductory Remarks ....... . 1 G.M. Lenoir, H. Land, L.F. Parada, J.M. Cunningham, R.A.'Weinberg: Activated Oncogenes in Burkitt's Lymphoma. . . . . . . . . 6 J.R. Nevins, M.J. Imperiale, H.-T. Kao, S. Strickland, L.T. Feldman: Detection of an Adenovirus E1A-like Activity in Mammalian Cells . . . . . . . . . . . . . . . . . . . . 15 N. Glaichenhaus, C. Galup, E. Mougneau, F. Cuzin: Does the Large T Protein of Polyoma Virus Regulate the Expression of the Celluar myc Gene? ... ,. . . . . . . . . . . . . . . . . . . . . . .. 20 M. Pawlita, L. Mosthaf, A. Clad, P. Gruss: Genome Structure and Host Range Restriction of the Lymphotropic Papovavirus (LPV): Identification of a Viral Lymphocyte Specific Enhancer Element. Wi th 3 Fi gures. . . . . . . . . . . . . . . . . . . . . . . . 26 M.-A. Lane, H.A.F. Stephens, K.M. Doherty, M.B. Tobin: Tlym-I, a Stage Specific Transforming Gene Shares Homology with MHC I Region Genes. . . . .. ....... . . . . . . . 31 G.M. Cooper: Structural and Functional Analysis of ras and Blym Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . .. 34 S. Lavu, J.F. Mushinski, G.L.C. Shen-Ong, M. Potter E.P. Reddy: Structural Organization of Mouse c-myb Locus and the Mechanism of its Rearrangement in ABP~-2 Tumor Line Induced by Pristane and Abelson Murine Leukemia Virus. With 3 Figures. . . . . . .. 37 G.L.C. Shen-Ong, E.P. Reddy, M. Potter, J.F. Mushinski: Disruption and Activation of the c-myb Locus by M-MuLV Insertion in Plasmacytoid Lymphosarcomas Induced by Pristane and Abelson Viruses. With 3 Figures. . . . . . . . . . . . . . . . . . . . . 41 E.H. Humphries, T.W. Baba: Follicular Hyperplasia in the Pre lymphomatous Avian Bursa: Relationship to the Incidence of B-Cell Lymphomas. With 3 Figures .................... 47 Growth Factors in B-Cell Neoplasia F. Melchers: Multiple Steps in the Transformation of Normal B Cells Towards Neoplasia. With i Figure. . . . . . . . . . 56 L.M. Neckers: Transferrin Receptors Regulate Proliferation of Normal and Malignant B Cells. With 5 Figures. . . . . . . . . 62 K.H. Brooks, W.A. Kuziel, P.W. Tucker, J.W. Uhr, E.S. Vitetta: Cloned Neoplastic B Cells Release a Growth Factor Which Augments Lymphokine-Mediated Proliferation of Normal B Cells ....... 69 x B. Subbarao, F. Melchers: The Action of an Lyb2.1-Specific Monoclonal Antibody in Soluble or Immobilized Form on Resting and Activated B Cells. . . . . . . . . . . . . . . . . . . . 72 L.F. Mayer, C. Thompson, S.M. Fu, H.G. Kunkel: T Cell Factors Regulating B Cell Activation and Differentiation. With 1 Figure 77 J.N. Ihle, H.C. Morse III, J. Keller, K.L. Holmes: Interleukin 3 Dependent Retrovirus Induced Lymphomas: Loss of the Ability to Terminally Differentiate in Response to Differentiation Factors . . . . . . . . . . . . .. ........ 86 A.L. DeFranco: Growth Regulation of a B-Cell Lymphoma via the Anti gen Receptor. . . . . . . . . . . . . . . . . . . . . . . 92 T.A. Waldmann, C.K. Goldman, W.J. Leonard, J.M. Depper,R.J. Robb, S.J. Korsmeyer, W.C. Greene: Interleukin-2 Receptors on Activated Malignant and Normal B-Cells. . . . . . . . . . . . . . . . . 96 J.J. Mond, C. Thompson, M. Schaefer, F.D. Finkelman, R. Robb: Immuno Affinity Purified Interleukin 2 (IL2) Induces B Cell Growth. . . . . . . . . . . . . . . . . . . . . . . . . .. .. 102 P.W. Kincade, H. Jyonouchi, K.S. Landreth, D. Engelhard, M.H. Beare, G. Lee, R.A. Good: Factors Affecting Normal and Malignant B Lymphocyte Precursors. . . . . . . . . . . .. . 104 J. Stavnezer, J. Abbott, S. Sirlin: Immunoglobulin Heavy Chain Switching in Cultured 1.29 Murine B Lymphoma Cells: Commitment to an IgA or IgE Switch. With 4 Figures.. ........ 109 Regulation of myc Gene Expression in Normal and Neoplastic Cells K. Kelly, B. Cochran, C. Stiles, P. Leder: The Regulation of c-myc by Growth Signals. With 4 Figures ............. 117 J.E. McCormack, R.B. Kent, V.H. Pepe, M. Dean, A. Marshak- Rothstein, G.E. Sonenshein: Immune Regulation of the c-myc Oncogene in a Murine B Lymphoma. With 4 Figures ..... . . . 127 C.M. Croce, J. Erikson, A. ar-Rushdi, D. Aden, K. Nishikura: The Translocated c-myc Oncogene of Burkitt Lymphoma is Differentially Regulated in Lymphoblastoid vs Plasma Cells With 5 Figures ...................... 133 Mechanism of myc Gene Activation J.Q. Yang, J.F. Mushinski, L.W. Stanton, P.O. Fahrlander, P.C. Tesser, K.B. Marcu: Modes of c-myc Oncogene Activation in Murine Plasmacytomas. With 2 Figures. . . . . . . . . . 146 W. Dunnick, J. Baumgartner, L. Fradkin, C. Schultz: DNA Sequences Involved in the Rearrangement and Expression of the Murine c-myc Gene. With 2 Figures ............... . ..... 154 S. Cory, S. Gerondakis, L.M. Corcoran, o. Bernard, E. Webb, J.M. Adams: Activation of the c-myc Oncogene in Band T Lymphoid Tumors .............................. 161 XI T.H. Rabbitts, R. Baer, M. Davis, A. Forster, P.H. Hamlyn, S. Malcolm: The c-myc Gene Paradox in Burkitt's Lymphoma Chromosomal Translocation. With 3 Figures. . . . . . . . . 166 M.M. Nau, D.N. Carney, J. Battey, B. Johnson, C. Little,A.Gazdar, J.D. Minna: Amplification, Expression, and Rearrangement of c-myc and N-myc Oncogenes in Human Lung Cancer. . . . . 172 F. Wiener: Chromosomal Aberrations in Murine Plasmacytomas. With 1 Fi gure . . . . . . . . . . . . . . . . . . . . . . . 178 U. Siebenlist, L. Hennighausen, J. Battey, P. Leder: Chromatin Structural Changes in the Putative Regulatory Region of c-myc Accompany the Translocation in a Burkitt Lymphoma. With 5 Figures 183 M. Shapiro and M. Weigert: Aberrant Rearrangements at the Murine Light Chain Locus in Plasmacytomas. With 1 Figure ........ 190 The myc Gene Product R.N. Eisenman, S.R. Hann: myc-Encoded Proteins of Chickens and Men. Wi th 1 Fi gure. . . . . . . . . . . . . . . . . . . . . .. 192 K. Moelling, T. Benter, T. Bunte, E. Pfaff, W. Deppert, J.M.Egly, N.B. Miyamoto: Properties of the myc-Gene Product: Nuclear Association, Inhibition of Transcription and Activation in Stimulated Lymphocytes. With 6 Figures .............. 198 In Vitro Culture of B Lymphocytes H.C. Morse III: Introduction to Long-Term Cultures of Normal B Lymphocytes . . . . . . . . . . . . .. . .......... 208 H.C. Morse III, M.C. Lamers, E.K. Rudikoff, W.F. Davidson: Characteristics of Continuous in vitro Lines of BALB/c and NZB B Cells. . . . . . . . . . . . . . . . . . . . . . . . . .. 210 J.I. Kurland, O.N. Witte: Development of Cellsofthe B-Lymphocyte Lineage in Longterm Culture. With 1 Figure . . . . . . . .. 217 K.L. Holmes, H.C. Morse III: Coexpression of Lyb-2 and Mac-l by Murine Lymphomas and Subpopulations of Normal Spleen and Bone Marrow Cells. With 1 Figure. . . . . . . . . . . . . 224 R.R. Hardy, K. Hayakawa, L.A. Herzenberg, H.C. Morse III, W.F. Davidson, L.A. Herzenberg: Ly-l as a Differentiation Antigen on Normal and Neoplastic B Cells. With 1 Figure ......... 231 J. Braun, J.-M. Kiely, E.R. Unanue: Propagation of B Lymphocytes in Vitro. . . .. . ........ 237 Potential New Systems for the Generation of B Cell Tumors W.Y. Langdon, J.W. Hartley, K.L. Holmes, T.N. Frederickson, H.C. Morse III: Identification of a Transforming Virus from a Lymphoma of a Mouse Infected with a Wild Mouse Retrovirus With 2 Figures ..................... " " 241